Efficient process for the preparation of sitagliptin through a very effective preparation of the intermediate 2,4,5-trifluorophenylacetic acid

Abstract

Object of the present invention is an efficient process for the preparation of the active pharmaceutical ingredient Sitagliptine and the 2,4,5-trifluorophenylacetic acid (TFAA) and salt thereof, which is a key intermediate for the synthesis of Sitagliptine.

The invention claimed is: 
     
       1. A process for the preparation of Sitagliptin of formula (I) or salt thereof: 
       
         
           
           
               
               
           
         
       
       comprising:
 A) preparing 2,4,5-trifluorophenylacetic acid of formula (II) or salt thereof: 
 
       
         
           
           
               
               
           
         
       
       by directly converting the compound of (III): 
       
         
           
           
               
               
           
         
       
       to the compound of formula (II) by reduction reaction; and
 B) converting the 2,4,5-trifluorophenylacetic acid of formula (II) to Sitagliptin of formula (I) or salt thereof. 
 
     
     
       2. The process according to  claim 1 , wherein step B) is carried out by:
 C) converting the 2,4,5-trifluorophenylacetic acid of formula (II) obtained in step A) to form the Ketoamide of formula (IV): 
 
       
         
           
           
               
               
           
         
         D) aminating the Ketoamide of formula (IV) produced in step C) to give the Enamine Amide of formula (V): 
       
       
         
           
           
               
               
           
         
       
       and
 E) converting the Enamine Amide of formula (V) obtained in step D) to Sitagliptin of formula (I): 
 
       
         
           
           
               
               
           
         
       
       or by means of the alternative method for obtaining Sitagliptin of formula (I) consisting of the following steps:
 D1) enzymatically converting the Ketoamide of formula (IV), obtained in the step C), to Sitagliptin of formula (I): 
 
       
         
           
           
               
               
           
         
       
     
     
       3. The process according to  claim 1 , wherein the compound of formula (III): 
       
         
           
           
               
               
           
         
       
       is prepared by:
 a) acylating the 1,3,4-trifluorobenzene of formula (VI): 
 
       
         
           
           
               
               
           
         
       
       with dichloroacetylchloride to give the compound of formula (VII): 
       
         
           
           
               
               
           
         
       
       and
 b) converting the compound of formula (VII) to the compound of formula (III): 
 
       
         
           
           
               
               
           
         
       
     
     
       4. The process according to  claim 1 , wherein the reduction reaction of step A) is carried out in presence of iodide catalyst. 
     
     
       5. The process according to the  claim 4 , wherein the iodide catalyst is selected from the group consisting of iodine, sodium iodide, potassium iodide, hydroiodic acid, lithium iodide, and ammonium iodide. 
     
     
       6. The process according to  claim 5 , wherein the iodide catalyst is sodium iodide. 
     
     
       7. The process according to  claim 5 , wherein the iodide catalyst is iodine. 
     
     
       8. The process according to  claim 1 , wherein the reduction reaction of step A) is carried out in presence of a phosphorus and/or sulphurous reductant. 
     
     
       9. The process according to  claim 8 , wherein the phosphorus and/or sulphurous reductant is selected from the group consisting of phosphorous acid, hypophosphorous acid, pyrophosphoric acid, triphosphoric acid, trimetaphosphoric acid, hypophosphoric acid, red phosphorus, sulfurous acid, pyrosulfurous acid, peroxymonosulfuric acid, and hyposulfurous acid. 
     
     
       10. The process according to the  claim 8 , wherein the phosphorus and/or sulphurous reductant is phosphorous acid. 
     
     
       11. The process according to  claim 1 , wherein the reduction reaction of step A) is carried out in an acid solvent or an aqueous acid mixture thereof. 
     
     
       12. The process according to the  claim 11 , wherein the acid solvent or an aqueous acid mixture thereof is selected from the group consisting of hydrobromic acid, acetic acid, and methansulphonic acid. 
     
     
       13. The process according to  claim 1 , wherein the reduction reaction of step A) is carried out in presence of iodide catalyst and with a phosphorus and/or sulphurous reductant and is carried out in an acid solvent or an aqueous acid mixture thereof. 
     
     
       14. The process according to  claim 13 , wherein the acid solvent or an aqueous acid mixture thereof is selected from the group consisting of hydrobromic acid, acetic acid and methansulphonic acid. 
     
     
       15. The process according to  claim 13 , wherein the iodide catalyst is sodium iodide, the phosphorus and/or sulphurous reductant is phosphorous acid, and the acid solvent or an aqueous acid mixture thereof is selected from the group consisting of hydrobromic acid, acetic acid and methansulphonic acid. 
     
     
       16. The process according to  claim 14 , wherein the acid solvent or an aqueous acid mixture thereof is methanesulphonic acid. 
     
     
       17. A process for the preparation of 2,4,5-trifluorophenylacetic acid of formula (II) or salt thereof: 
       
         
           
           
               
               
           
         
       
       by comprising directly converting the compound of (III): 
       
         
           
           
               
               
           
         
       
       to the compound of formula (II), 
       wherein said direct conversion is carried out by reduction reaction. 
     
     
       18. The process according to  claim 17 , wherein the reduction reaction is carried out in the presence of iodide catalyst. 
     
     
       19. The process according to  claim 17 , wherein the reduction reaction is carried out in the presence of a phosphorus and/or sulphurous reduction. 
     
     
       20. The process according to  claim 17 , wherein the reduction reaction of step A) is carried out in an acid solvent or an aqueous acid mixture thereof.